Association of GBA Genotype With Motor and Functional Decline in Patients With Newly Diagnosed Parkinson Disease.
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ABSTRACT: Objective
To establish the significance of glucocerebrosidase gene (GBA) carrier status on motor impairment in a large cohort of patients with incident Parkinson disease (PD).Methods
Three European population-based studies followed 528 patients with PD from diagnosis. A total of 440 with genomic DNA from baseline were assessed for GBA variants. We evaluated motor and functional impairment annually using the Unified Parkinson's Disease Rating Scale (UPDRS) motor and activities of daily living (ADL) sections. Differential effects of classes of GBA variants on disease progression were evaluated using mixed random and fixed effects models.Results
A total of 387 patients with idiopathic disease (age at baseline 70.3 ± 9.5 years; 60.2% male) and 53 GBA carriers (age at baseline 66.8 ± 10.1 years; 64.2% male) were included. The motor profile of the groups was clinically indistinguishable at diagnosis. GBA carriers showed faster annual increase in UPDRS scores measuring ADL (1.5 point per year, 95% confidence interval [CI] 1.1-2.0) and motor symptoms (2.2 points per year, 95% CI 1.3-3.1) compared to noncarriers (ADL, 1.0 point per year, 95% CI 0.9-1.1, p = 0.003; motor, 1.3 point per year, 95% CI 1.1-1.6, p = 0.007). Simulations of clinical trial designs showed that recruiting only GBA carriers can reduce trial size by up to 65% compared to a trial recruiting all patients with PD.Conclusion
GBA variants are linked to a more aggressive motor disease course over 7 years from diagnosis in patients with PD. A better understanding of PD progression in genetic subpopulations may improve disease management and has direct implications for improving the design of clinical trials.
SUBMITTER: Maple-Grodem J
PROVIDER: S-EPMC8055329 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveVariants in the glucocerebrosidase (GBA) gene are the most common and significant risk factor for Parkinson's disease (PD). However, the impact of GBA variants on PD disease progression in the Chinese population remains unclear. This study aimed to explore the significance of GBA status on motor and cognitive impairment in a longitudinal cohort of Chinese patients with PD.MethodsThe entire GBA gene was screened by long-range polymerase chain reaction (LR-PCR) and next generation sequencing (NGS). A total of 43 GBA-related PD (GBA-PD) and 246 non-GBA-mutated PD (NM-PD) patients with complete clinical data at baseline and at least one follow-up were recruited for this study. The associations of GBA genotype with rate of motor and cognitive decline, as measured by Unified PD Rating Scale (UPDRS) motor and Montreal Cognitive Assessment (MoCA), were assessed by linear mixed-effect models.ResultsThe estimated (standard error, SE) UPDRS motor [2.25 (0.38) points/year] and MoCA [-0.53 (0.11) points/year] progression rates in the GBA-PD group were significantly faster than those in the NM-PD group [1.35 (0.19); -0.29 (0.04) points/year; respectively]. In addition, the GBA-PD group showed significantly faster estimated (SE) bradykinesia [1.04 (0.18) points/year], axial impairment [0.38 (0.07) points/year], and visuospatial/executive [-0.15 (0.03) points/year] progression rates than the NM-PD group [0.62 (0.10); 0.17 (0.04); -0.07 (0.01) points/year; respectively].ConclusionGBA-PD is associated with faster motor and cognitive decline, specifically greater disability in terms of bradykinesia, axial impairment, and visuospatial/executive function. Better understanding of GBA-PD progression may help predict prognosis and improve clinical trial design.
| S-EPMC9950580 | biostudies-literature
Project description:Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets.To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression.The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state.Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site.Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (??=?4.65; 95% CI, 1.72-7.58; P?=?.002), E326K (??=?3.42; 95% CI, 0.66-6.17; P?=?.02), and GBA variants combined as a single group (??=?4.01; 95% CI, 1.95-6.07; P?=?1.5?×?10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (??=?0.38; 95% CI, 0.23-0.53; P?=?.01) and E326K (??=?0.64; 95% CI, 0.43-0.86; P?=?.002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P?=?.01) and GBA variant carriers (15 of 39 [38.5%]; P?=?.04) progressed to mild cognitive impairment or dementia.GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.
| S-EPMC5056861 | biostudies-literature
Project description:ImportanceGenetic factors have a well-known influence on Parkinson disease (PD) susceptibility. The largest genome-wide association study (GWAS) identified 26 independent single-nucleotide polymorphisms (SNPs) associated with PD risk. Among patients, the course and severity of symptom progression is variable, and little is known about the potential association of genetic factors with phenotypic variance.ObjectiveTo assess whether GWAS-identified PD risk SNPs also have a cumulative association with the progression of cognitive and motor symptoms in patients with PD.Design, setting, and participantsThis longitudinal population-based cohort study of 285 patients of European ancestry with incident PD genotyped 23 GWAS SNPs. One hundred ninety-nine patients were followed up for a mean (SD) of 5.3 (2.1) years for progression (baseline: June 1, 2001, through November 31, 2007; follow-up: June 1, 2007, through August 31, 2013, with mortality surveillance through December 31, 2016); 57 patients had died or were too ill for follow-up, and 29 withdrew or could not be contacted. Movement disorder specialists repeatedly assessed PD symptom progression.Main outcomes measuresThe combined association of PD risk loci, after creating a weighted polygenic risk score (PRS), with cognitive decline, motor progression, and survival, relying on Cox proportional hazards regression models and inverse probability weights to account for censoring.ResultsOf the 285 patients undergoing genotyping, 160 were men (56.1%) and 125 were women (43.9%); the mean (SD) age at diagnosis was 69.1 (10.4) years. The weighted PRS was associated with significantly faster cognitive decline, measured by change in the Mini-Mental State Examination (hazard ratio [HR] per 1 SD, 1.44; 95% CI, 1.00-2.07). The PRS was also associated with faster motor decline, measured by time to Hoehn & Yahr Scale stage 3 (HR, 1.34; 95% CI, 1.00-1.79) and change in Unified Parkinson's Disease Rating Scale part III score (HR, 1.42; 95% CI, 1.00-2.01).Conclusions and relevanceSusceptibility SNPs for PD combined with a cumulative PRS were associated with faster motor and cognitive decline in patients. Thus, these genetic markers may be associated with not only PD susceptibility but also disease progression in multiple domains.
| S-EPMC5885856 | biostudies-literature
Project description:The lysosomal enzyme glucocerebrosidase (GCase), encoded by GBA, has an important role in Parkinson disease (PD). GBA mutation carriers have an increased risk for PD, earlier age at onset, faster progression, and various nonmotor symptoms including cognitive decline, REM sleep behavior disorder, hyposmia, and autonomic dysfunction.(1) Furthermore, GCase enzymatic activity is reduced in the peripheral blood(2) and brain(3) of noncarrier, sporadic PD patients. Biallelic GBA mutations, which have been classified as "severe" or "mild," may cause Gaucher disease (GD), a lysosomal storage disorder. Mild mutations may lead to GD type 1, and 2 severe mutations result in neuronopathic GD (type 2 and type 3).(4) There are 2 GBA variants, p.E326K and p.T369M, which do not cause GD in homozygous carriers, but may modify GCase activity and GD phenotype. It is now clear that p.E326K is a risk factor for PD,(5) but whether p.T369M is associated with PD is still controversial. In some studies, the p.T369M substitution was associated with PD,(6) while in others it had similar or increased frequency in controls. Of interest, it was recently demonstrated that the GBA p.T369M substitution was associated with reduced enzymatic activity in patients with PD and controls compared with that in noncarriers (7.64 vs 11.93 ?mol/L/h, p < 0.001).(2) Of interest, it was even lower than the average enzymatic activity of the p.E326K substitution, which was 9.81 ?mol/L/h. Because clinical trials on GBA-associated PD are ongoing, and because treatment specifically targeting GBA is likely to be available in the future, it is important to determine whether the GBA p.T369M substitution is associated with PD.
| S-EPMC5017539 | biostudies-literature
Project description:ImportanceDespite a hypothesis that harboring a leucine-rich repeat kinase 2(LRRK2) G2019S variation and a glucocerebrosidase (GBA) variant would have a combined deleterious association with disease pathogenesis, milder clinical phenotypes have been reported in dual LRRK2 and GBA variations Parkinson disease (PD) than in GBA variation PD alone.ObjectiveTo evaluate the association of LRRK2 G2019S and GBA variants with longitudinal cognitive and motor decline in PD.Design, setting, and participantsThis longitudinal cohort study of continuous measures in LRRK2 PD, GBA PD, LRRK2/GBA PD, and wild-type idiopathic PD used pooled annual visit data ranging from 2004 to 2019 from the Mount Sinai Beth Israel, Parkinson Disease Biomarker Program, Harvard Biomarkers Study, Ashkenazi Jewish-LRRK2-Consortium, Parkinson Progression Marker Initiative, and SPOT-PD studies. Patients who were screened for GBA and LRRK2 variations and completed either a motor or cognitive assessment were included. Data were analyzed from May to July 2020.Main outcomes and measuresThe associations of LRRK2 G2019S and GBA genotypes on the rate of decline in Montreal Cognitive Assessment (MoCA) and Movement Disorders Society-Unified Parkinson Disease Rating Scale-Part III scores were examined using linear mixed effects models with PD duration as the time scale.ResultsAmong 1193 individuals with PD (mean [SD] age, 66.6 [9.9] years; 490 [41.2%] women), 128 (10.7%) had GBA PD, 155 (13.0%) had LRRK2 PD, 21 (1.8%) had LRRK2/GBA PD, and 889 (74.5%) had idiopathic PD. Patients with GBA PD had faster decline in MoCA than those with LRRK2/GBA PD (B [SE], -0.31 [0.09] points/y; P < .001), LRRK2 PD (B [SE], -0.33 [0.09] points/y; P < .001), or idiopathic PD (B [SE], -0.23 [0.08] points/y; P = .005). There was a LRRK2 G2019S × GBA interaction in MoCA decline (B [SE], 0.22 [0.11] points/y; P = .04), but not after excluding severe GBA variations (B [SE], 0.12 [0.11] points/y; P = .28). Patients with GBA PD had significantly worse motor progression compared with those with idiopathic PD (B [SE], 0.49 [0.22] points/y; P = .03) or LRRK2 PD (B [SE], 0.77 [0.26] points/y; P = .004).Conclusions and relevanceThese findings suggest that longitudinal cognitive decline in patients with GBA PD was more severe than in those with LRRK2/GBA PD, which more closely resembled LRRK2 PD. This further supports the notion of a dominant association of LRRK2 on GBA in individuals who carry both and raises the possibility of an LRRK2 × GBA interaction. However, the biological basis of a dominant association or interaction is not clear and is apparently contrary to basic investigations. Study of a larger cohort of individuals with severe GBA variation is warranted.
| S-EPMC8060834 | biostudies-literature
Project description:Background and purposeVariants in the glucocerebrosidase (GBA) gene are recognized as a common and important genetic risk factor for Parkinson disease (PD). However, the impact of variant severity on the clinical phenotype of PD in the Chinese population remains unclear. Thus, the present study aimed to determine the frequency of GBA-related PD (GBA-PD) and the relationship of GBA variant severity with clinical characteristics in a large Chinese cohort.MethodsLong-range polymerase chain reaction and next generation sequencing were performed for the entire GBA gene. GBA variant severity was classified into five classes: mild, severe, risk, complex, and unknown.ResultsAmong the total 737 PD patients, 47 GBA variants were detected in 79 (10.72%) patients, and the most common GBA variants were R163Q, L444P, and R120W. Complete demographic and clinical data were obtained for 673 patients, which revealed that 18.50% of early onset PD patients had GBA variants. Compared with patients without GBA variants, GBA-PD patients experienced PD onset an average of 4 years earlier and had more severe motor and nonmotor symptoms. Patients carrying severe and complex variants had a higher burden of nonmotor symptoms, especially depression, and more mood/cognitive and gastrointestinal symptoms than patients carrying mild variants.ConclusionsGBA-PD is highly prevalent in the Chinese population. The severity of GBA variants underlies distinct phenotypic spectrums, with PD patients carrying severe and complex variants seeming to have similar phenotypes. PD patient stratification by GBA variant severity should become a prerequisite for selecting specific treatments.
| S-EPMC9303336 | biostudies-literature
Project description:Variants in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for Parkinson disease (PD). These include pathogenic variants causing Gaucher disease (GD) (divided into "severe," "mild," or "complex"-resulting from recombinant alleles-based on the phenotypic effects in GD) and "risk" variants, which are not associated with GD but nevertheless confer increased risk of PD. As a group, GBA-PD patients have more severe motor and nonmotor symptoms, faster disease progression, and reduced survival compared with noncarriers. However, different GBA variants impact variably on clinical phenotype. In the heterozygous state, "complex" and "severe" variants are associated with a more aggressive and rapidly progressive disease. Conversely, "mild" and "risk" variants portend a more benign course. Homozygous or compound heterozygous carriers usually display severe phenotypes, akin to heterozygous "complex" or "severe" variants carriers. This article reviews genotype-phenotype correlations in GBA-PD, focusing on clinical and nonclinical aspects (neuroimaging and biochemical markers), and explores other disease modifiers that deserve consideration in the characterization of these patients.
| S-EPMC8264189 | biostudies-literature
Project description:ObjectiveTo develop a prognostic model to predict disease outcomes in individual patients with Parkinson disease (PD) and perform an external validation study in an independent cohort.MethodsModel development was done in the Comorbidity and Aging in Rehabilitation Patients: The Influence on Activities (CARPA) cohort (Netherlands). External validation was performed using the Cambridgeshire Parkinson's Incidence from GP to Neurologist (CamPaIGN) cohort (UK). Both are longitudinal incident cohort studies that prospectively followed up patients with PD from the time of diagnosis. A composite outcome measure was made in which patients were classified as having an unfavorable prognosis when they had postural instability or dementia at the 5-year assessment (or at the last assessment before loss to follow-up), or had died before this time. The final model was derived with a backward selection strategy from candidate predictor variables that were measured at baseline.ResultsIn the resulting model, higher patient age, higher Unified Parkinson's Disease Rating Scale motor examination axial score, and a lower animal fluency score were all associated with a higher probability of an unfavorable outcome. External validation confirmed good discriminative ability between favorable and unfavorable outcomes with an area under the receiver operating characteristic curve of 0.85 (95% confidence interval 0.77-0.93) and a well-calibrated model with a calibration slope of 1.13 and no significant lack of fit (Hosmer-Lemeshow test: p = 0.39).ConclusionWe constructed a model that allows individual patient prognostication at 5 years from diagnosis, using a small set of predictor variables that can easily be obtained by clinicians or research nurses.
| S-EPMC4799715 | biostudies-literature
Project description:Low CSF ?-amyloid 1-42 has been associated with cognitive decline in advanced Parkinson's disease; data from a single cohort suggest ?-amyloid 1-42 may be an early marker of cognitive impairment. Newly diagnosed Parkinson's participants (mean duration, 6.9 months) in the Parkinson's Progression Markers Initiative (n = 341) were assessed at baseline (untreated state) and followed for 2 years. CSF ?-amyloid 1-42, ?-synuclein, total tau, and tau phosphorylated at threonine 181 were collected at baseline. Participants were classified as having cognitive impairment (CI) if scores on two of six cognitive tests were 1.5 standard deviations below the standardized mean based on published norms in healthy controls. Multivariable regression analyses were used to determine the association between baseline CSF markers with cognitive impairment, defined by neuropsychological testing performance at 2-year follow-up. Fifty-five participants (16.1 %) had CI at baseline and were not included in further analyses. Thirty-seven of the 286 participants without CI at baseline (12.9 %) developed CI at 2 years. Participants with CI at 2 years had significantly lower mean baseline CSF ?-amyloid 1-42 levels than non-CI participants (343.8 vs. 380.4 pg/mL, p < 0.01); no significant difference was seen for ?-synuclein, T-tau, or P-tau 181. In a regression model of 286 participants without baseline CI adjusted for age, gender, disease duration, education, motor severity, and depression status, lower baseline ?-amyloid 1-42 levels were associated with higher odds of CI at 2 years. (OR(10pg/mL) = 1.04, 95 % CI 1.01-1.08, p < 0.05). CSF ?-amyloid 1-42 level at disease onset is an independent predictor of cognitive impairment in early Parkinson's disease.
| S-EPMC4738011 | biostudies-literature
Project description:Saposin C (SapC), encoded by PSAP, is required for the activity of glucocerebrosidase, encoded by GBA. Although GBA mutations have been studied thoroughly in Parkinson disease (PD), genetic studies on SapC are still lacking. PSAP was sequenced in 1123 PD patients and 1153 controls, and data from additional 1167 patients and 1685 controls were examined. A total of 6 patients had SapC mutations in the 2 combined cohorts, but no statistically significant association after correction for multiple comparisons was found. Larger studies are necessary to examine the role of very rare SapC variants in PD.
| S-EPMC6215722 | biostudies-literature